Biological activity of modified and exchanged 2-amino-5-nitrothiazole amide analogues of nitazoxanide

Abstract

Head group analogues of the antibacterial and antiparasitic drug nitazoxanide (NTZ) are presented. A library of 39 analogues was synthesized and assayed for their ability to suppress growth of Helicobacter pylori, Campylobacter jejuni, Clostridium difficile and inhibit NTZ target pyruvate:ferredoxin oxidoreductase (PFOR). Two head groups assayed recapitulated NTZ activity and possessed improved activity over their 2-amino-5-nitrothiazole counterparts, demonstrating that head group modification is a viable route for the synthesis of NTZ-related antibacterial analogues.

Figure 1

Nitro heterocyclic drugs.

Figure 2

Pyruvate:ferredoxin oxidoreductase (PFOR) enzymatic reaction. PFOR catalyzes the oxidative decarboxylation of pyruvate producing Acetyl-CoA and CO₂ requiring the electron acceptors ferredoxin (Fd) or flavodoxin (Fld). Oxidation of Fd/Fld is accomplished by NADP oxidases or hydrogenases, respectively. Solid arrows indicate the forward reaction; hollow arrows indicate reverse reaction.

Figure 3

Pyruvate binding to activated vitamin co-factor thiamine pyrophosphate (TPP) which then is consumed in the production of acetyl-CoA. NTZ is thought to bind to TPP in an analogous fashion to pyruvate and prevent its binding thereby inhibiting the enzymatic reaction.

Figure 4

Composition of library separated as head group and tail groups.